Methods for enhancing exposure therapy using pairing with vagus nerve stimulation

ABSTRACT

Disclosed is a method of enhancing exposure therapy including providing an exposure therapy to a patient and stimulating the patient&#39;s vagus nerve at the same time as the exposure therapy. Also disclosed is a post-traumatic stress disorder therapy method including providing an exposure event to a patient and stimulating the patient&#39;s vagus nerve during the exposure event. Also disclosed is a phobia disorder therapy method including providing an extinction event to a patient and stimulating the patient&#39;s vagus nerve during the exposure event. Also disclosed is an obsessive compulsive disorder therapy method including providing a therapy event to a patient and stimulating the patient&#39;s vagus nerve during the therapy event. Also disclosed is an addiction disorder therapy method including providing a therapy event to a patient and stimulating the patient&#39;s vagus nerve during the therapy event.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.14/808,509, filed Jul. 24, 2015, now U.S. Pat. No. 10,213,577, which isa Divisional of U.S. patent application Ser. No. 13/095,570, filed onApr. 27, 2011, now U.S. Pat. No. 9,089,703, granted Jul. 28, 2015, whichclaims the benefit of U.S. Provisional Patent Application No.61/328,621, filed Apr. 27, 2011. U.S. patent application Ser. No.13/095,570 is also a Continuation-In-Part of U.S. patent applicationSer. No. 12/485,040, filed Jun. 15, 2009, now U.S. Pat. No. 9,089,707,granted Jul. 28, 2015, which claims the benefit of: U.S. ProvisionalPatent Application No. 61/077,648, filed Jul. 2, 2008; U.S. ProvisionalPatent Application No. 61/078,954, filed Jul. 8, 2008; U.S. ProvisionalPatent Application No. 61/086,116, filed Aug. 4, 2008; and U.S.Provisional Patent Application No. 61/149,387, filed Feb. 3, 2009. Allof these applications are incorporated herein by reference as ifreproduced in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

REFERENCE TO A MICROFICHE APPENDIX

Not applicable.

BACKGROUND

Exposure therapy is a recognized treatment for anxiety disorders such asphobia, post-traumatic stress disorder (PTSD), obsessive-compulsivedisorder, and relapse of drug abuse. Adjunct treatment with memoryenhancing drugs has been shown to enhance the efficacy of exposuretherapy in the treatment of phobia disorder. Vagus Nerve Stimulation(VNS) has been shown to enhance the consolidation of new memories,likely through modulation of brain plasticity. VNS paired precisely witha specific tone induces cortical plasticity and has been used toeffectively treat tinnitus in rats. Clinical trials examining tinnitustreatment in humans are currently underway. Enhancement of exposuretherapy would have obvious implications for the treatment of anxietydisorders.

SUMMARY

For purposes of summarizing the disclosure, certain aspects, advantages,and novel features of the disclosure have been described herein. It isto be understood that not necessarily all such advantages may beachieved in accordance with any particular embodiment of the disclosure.Thus, the disclosure may be embodied or carried out in a manner thatachieves or optimizes one advantage or group of advantages as taughtherein without necessarily achieving other advantages as may be taughtor suggested herein.

In an embodiment, the disclosure includes a method of enhancing exposuretherapy comprising providing an exposure therapy to a patient andstimulating the patient's vagus nerve at the same time as the exposuretherapy.

In an embodiment, the disclosure includes a post-traumatic stressdisorder therapy method comprising providing an exposure event to apatient and stimulating the patient's vagus nerve during the exposureevent.

In an embodiment, the disclosure includes a phobia disorder therapymethod comprising providing an extinction event to a patient andstimulating the patient's vagus nerve during the exposure event.

In an embodiment, the disclosure includes an obsessive-compulsivedisorder therapy method comprising providing a therapy event to apatient and stimulating the patient's vagus nerve during the therapyevent.

In an embodiment, the disclosure includes an addiction disorder therapymethod comprising providing a therapy event to a patient and stimulatingthe patient's vagus nerve during the therapy event.

These and other features will be more clearly understood from thefollowing detailed description taken in conjunction with theaccompanying drawings and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of this disclosure, reference is nowmade to the following brief description, taken in connection with theaccompanying drawings and detailed description, wherein like referencenumerals represent like parts.

FIG. 1 is a graph showing VNS enhances extinction of fear-potentiatedstartle;

FIG. 2 is a graph showing VNS facilitates extinction of auditory fearconditioning; and

FIG. 3 is a graph showing VNS facilitates extinction when given twoweeks after auditory fear conditioning.

FIG. 4 is a simplified diagram depicting a stimulator, in accordancewith an embodiment;

FIG. 5 is a simplified diagram depicting a wireless stimulator, inaccordance with an embodiment;

FIG. 6 is a simplified diagram depicting a dual stimulatorconfiguration, in accordance with an embodiment; and

FIG. 7 is a simplified diagram depicting a multi-stimulatorconfiguration, in accordance with an embodiment.

DETAILED DESCRIPTION

It should be understood at the outset that although an illustrativeimplementation of one or more embodiments are provided below, thedisclosed systems and/or methods may be implemented using any number oftechniques, whether currently known or in existence. The disclosureshould in no way be limited to the illustrative implementations,drawings, and techniques illustrated below, including the exemplarydesigns and implementations illustrated and described herein, but may bemodified within the scope of the appended claims along with their fullscope of equivalents. The present application describes severalembodiments, and none of the statements below should be taken aslimiting the claims generally.

Typically, conditioned fear associations are formed (consolidated), andthen replaced with new associations (extinction). Problems manifest whenconditioned fears form but are not naturally extinguished. Consolidationand extinction are related processes. Normal extinction processes dependon the consolidation of new memories. Vagus nerve stimulation has beenshown to improve memory consolidation.

Memory disorders like PTSD can take months to develop following theinitial exposure to the traumatic events and even longer for sufferersto seek treatment. Potential treatments should be effective wheninitiated long after a trauma. Extinction training may be performed twoweeks after induction of the initial fear conditioning. Since thespontaneous recovery of fear memories after extinction has been observedin human and nonhuman animals, it was also examined whether the effectsof VNS treatment are long lasting. For this purpose, animals were testeda second time, two weeks after extinction training.

VNS is approved by the Food and Drug Administration (FDA) for treatmentof intractable epilepsy and depression. Beneficial effects of VNS suchas enhanced cognition in patients with epilepsy and Alzheimer's diseasehave been reported. By combining vagal stimulation with ExposureTherapy, the natural extinction process that protects most people fromdeveloping PTSD may be facilitated. The brain may be rehabilitated bytargeting the systems involved in the consolidation of the initialtraumatic memory.

Because of the tight temporal and spatial control associated with briefVNS, this approach may target more efficiently the brain areas andsynapses that support PTSD than using drug therapy. Since VNS is knownto decrease the stress response of the sympathetic nervous system, itmay increase the effectiveness of traditional talk therapy or emergingvirtual reality therapies by reducing the possibility that patients willassociate exposure therapy cues with anxiety.

The cause of PTSD remains unknown, but psychological and physicalalterations have been identified in PTSD patients that suggest VNStherapy would be highly effective at helping these particular patientsto extinguish traumatic associations. Several reports have identifiedevidence of an impaired ability to extinguish former associations inPTSD subjects. Long-term consolidation of emotionally arousing memoriesrequires vagus nerve-initiated activation of the nucleus of the solitarytract.

Accordingly, it is likely that impaired vagal tone would adverselyaffect consolidation of extinction memory. Decreased vagal tone has beenobserved in human subjects with PTSD. Low basal cortisol levels, adisconnection in the normal modulation of the amygdala by the medialprefrontal cortex, increased sympathetic, and decreased parasympathetictone have also been observed in PTSD patients.

Research findings demonstrate the potential for reversal of thesePTSD-associated abnormalities with VNS treatment. VNS enhances memoryconsolidation, modulates cortisol levels, increases norepinephrinerelease in both the amygdala and medial prefrontal cortex, and altersthe balance of sympathetic to parasympathetic activity in the autonomicnervous system.

The failure to naturally extinguish conditioned fears leads to PTSD andthe goal of Exposure Therapy is to extinguish such memories. Fearconditioning and extinction are readily quantifiable in laboratory ratsand extinction training is traditionally used as an animal model ofExposure Therapy. Thus, extinction training may be used in rats as amodel for Exposure Therapy for conducting tests of feasibility. Further,tests of VNS-induced cognitive enhancement revealed that similar VNSparameters also occur in rats and human patients.

Using two different measures of fear conditioning, it was found that VNSpairing produces better and improved rapid extinction of fear responses.VNS pairing enhances extinction even when administered about two weeksafter training, suggesting that even a relatively well-consolidatedmemory is responsive to the therapy. No evidence for spontaneousrecovery of fear after about two weeks was found.

Experiments were designed to determine if paired VNS therapy couldenhance the efficacy of extinction training in a rat model. It wasevaluated whether paired VNS enhances extinction in rats that wererecently trained on a fear-conditioning task. The efficacy of VNS whengiven about two weeks after the initial fear conditioning was alsoevaluated. This is relevant since most patients seek intervention afterthe conditioned fear fails to automatically extinguish over time. Thesensitivity of VNS-enhanced extinction to relapse was evaluated sincethe benefits of traditional exposure therapy are often transient.

Results demonstrated both enhanced and accelerated extinction. Twodifferent measures of fear conditioning were examined. Afear-potentiated startle task uses an accelerometer to measure thestartle response as an indicator of fear conditioning. Rats conditionedto fear a light demonstrated greater startle responses to an abruptburst of white noise in the presence of the light.

Both constant current and voltage controlled capacitive dischargestimulation were used to test auditory fear conditioning. Both wereeffective.

The results and findings indicate that exposure therapy can be enhancedby providing an exposure therapy to a patient while simultaneouslystimulating the patient's vagus nerve. The nature of the exposuretherapy may depend on the condition being treated. For example, forpost-traumatic stress disorder, the therapy event may be a sensoryrecreation of the traumatic event, presented in a controlledenvironment.

The precise timing of the paired VNS pulse may depend on the nature ofthe therapy event. The results indicate that the paired VNS pulse may begiven during the therapy rather than before or after, although someoverlap is not contraindicated. Where a trigger event can be identifiedin the therapy event, such as a tone or flash, the pairing can bederived from the trigger event.

Exposure therapy of this kind can be used to treat post-traumatic stressdisorder, phobic disorders, obsessive-compulsive disorder, addictiondisorders including addiction relapse, and other memory extinctiondisorders. VNS can be paired effectively with any of these knowntherapies.

With reference to FIG. 1 , a graph shows that after a single extinctionsession, rats that were given VNS paired with the conditioned stimulus(light) showed significantly lower startle responses than sham-treatedcontrols. In the auditory fear-conditioning paradigm, freezing is themeasure of fear conditioning. Conditioned rats freeze in the presence ofa tone that was associated with a foot-shock during training.

With reference to FIG. 2 , a graph shows that VNS-treated rats expressedless freezing after a single extinction session. Moreover, they achievedcomplete remission from freezing (freezing less than about 20% of thetest time) after three sessions, whereas sham-treated controls did notreach full remission and seemed to plateau after three extinctionsessions. These findings suggest that VNS pairing may enhance andaccelerate the effects of exposure therapy.

VNS enhances extinction after a single session (FIG. 1 ) and acceleratesremission of the fear response (FIG. 2 ). Fear potentiated startlescores were computed as [(startle amplitude on light-sound burst minussound burst-alone trials)/sound burst-alone trials]×100. An analysis ofvariances (ANOVA) revealed a significant effect and Fisher's post hoctest revealed a significant treatment effect after a single trial (usingFisher's protected least significant difference (PLSD) p=0.0221 vs. shamcontrol). Freezing scores (FIG. 2 ) were normalized to pre-VNS treatmentvalues and a repeated measures ANOVA (Subject (Stimulationtype)*treatment day) was used to assess differences over the treatmenttrials. Fisher's post hoc test was used to identify group differences.The effect of treatment day on freezing is significant F ((3, 24)=8.994,p<0.001). A post hoc analysis revealed a significant treatment effect ofexponential stimulation on freezing relative to sham controls (Fisher'sPLSD, p=0.0356). Spontaneous recovery of fear was not observed in eithergroup at about two weeks after completion of extinction trials. Theerror bars are standard error of the mean (SEM).

VNS-facilitated extinction remained after about two weeks. Treated ratswere significantly different from the control group at the two-week timepoint, suggesting that the effects of VNS were not transient.

With reference to FIG. 3 , the graph depicts the freezing scoresnormalized to pre-VNS treatment values and a repeated measures ANOVA(Subject (Stimulation type)*treatment day) was used to assessdifferences over the treatment trials. Fisher's post hoc test was usedto identify group differences. Consistent with an overall extinctioneffect, the effect of treatment day on freezing is significant F ((4,24)=26.662, p<0.001). A post hoc analysis revealed a significanttreatment effect of exponential stimulation on freezing relative to shamcontrols (Fisher's PLSD, p=0.0171). These findings are consistent withan enhancing effect of vagus nerve stimulation on extinction overrepeated treatment trials at about two weeks after conditioning. Theerror bars are SEM.

The results repeat literature findings in demonstrating that VNSenhances the ability of rats to learn and remember events. The taskdescribed below is taken as a fear-conditioning test.

The preliminary results were consistent with reports that VNS enhancesmemory. Ten Sprague-Dawley rats were implanted with VNS electrodes andstimulated. A single stimulation (0.5 microsecond (ms) biphasic pulses;20 Hertz (Hz); 30 seconds (s); 0.4 milliampere (mA)) of the vagus nervein rats immediately after the training trial enhanced memory for a fearconditioning task. These parameters were selected because they enhancedmemory in previous reports. We found that VNS-treated rats spentsignificantly more time avoiding the context where they received afoot-shock at about 48 hours earlier (p−0.017 vs. sham control,n=5/group). These findings suggest that VNS enhances the consolidationof the memory for the association between a context and foot-shock.

Extinction training is a commonly used animal model for ExposureTherapy. As in Exposure Therapy, animals undergoing extinction traininglearn to make new associations that compete with the old memories.

The next experiment demonstrated that paired VNS increases the rate ofextinction of fear memories in rats. This provides proof of concept forenhancing extinction. Extinction training was performed either about oneday or about two weeks after induction of the initial fear conditioning.This set of studies provides proof of concept that VNS may enhanceextinction long after the initial learned fear event. PTSD may takemonths to develop and even longer for sufferers to seek treatment. For atreatment to be useful, it must also be effective when initiated longafter a trauma. A third experiment examined the duration of the effectof VNS-enhanced fear extinction. Because the spontaneous recovery offear memories after extinction has been observed in human and non-humananimals, it may be important to examine whether the effects of VNS aidedextinction training are long lasting.

Each animal was initially anesthetized in an induction chamber filledwith isofluorane gas. When the anesthetic took effect, animals wereremoved from the induction chamber and fitted with a nose cone throughwhich isofluorane mixed with oxygen flows. Animals were shaved at theventral region of the neck just above the clavicle and from the base ofthe skull to just ventral to the eyes. Both regions were swabbed withabout 70% ethanol, then betadine. An incision was made on the top of thehead to expose the skull and two anchor screws were placed lateral ofbregma.

Biocompatible micro-renathane tubing (0.04 inch (in.) inner diameter(i.d.), 0.08 in. outer diameter (o.d.), 4 millimeter (mm) long) with alongitudinal slit was used as the electrode cuff.

Two about 7 centimeter (cm) long and about 0.006 in. diameter,TEFLON-insulated, multi-stranded platinum-iridium wires were inserted sothat each lead penetrated the cuff lumen and was looped securely aroundboth sides of the slit opening such that the wire within the cuff lumenwas uninsulated. Stimulating poles were separated by about 2 mm.

The stimulating cuff was connected to the implant and securely fastenedto the skull with dental acrylic. The vagus nerve was accessed at thecervical level through an incision made in the skin along the ventralmidline, approximately two cm in length to a depth where the firstsuperficial muscle layers become visible. The muscle layers wereseparated, exposing the vagus nerve and carotid artery. The stimulatingelectrode was tunneled subcutaneously to the incision site and placednear the nerve. The nerve was isolated from the connective tissue andplaced into the cuff electrode. To insure connectivity of theexperimental setup, about 0.2 mA stimulation was administered into thehead implant and cessation of breath was assayed.

Twenty rats were implanted with bipolar platinum iridium cuff electrodesaround the left vagus nerve. Rats were submitted to auditoryfear-conditioning in which a pure tone (about 30 s, about 80 decibel(dB), about 5 kilohertz (kHz)) was paired with a foot shock (about 0.5mA, about 1 s, co-terminating with tone) over about four trials/day, forabout two days, with about three, four, or five min inter-trial intervalbeginning about three min after being placed in the chamber. Abouttwenty-four hours later, rats were placed in the extinction contextagain. Under these conditions, when the tone was presented, animalswould freeze for a period of time. Percent time spent freezing (timespent freezing/total time in the behavioral apparatus), defined as theabsence of all non-respiratory movement, served as the index of fearmemory. This test trial was followed by further extinction 24 hourslater. Twenty “sham” control rats were implanted with vagal cuffelectrodes and were submitted to the same training and extinctionprotocols described above. Leads from the cuff to the stimulator wereattached during training; however, no stimulation was given to thiscontrol group. The experimental group was administered VNS (about 0.5 msbiphasic pulses; about 30 s; about 0.4 mA; about 20 Hz, or exponentialpulse) applied concurrently with the tone during extinction trials (4tone exposures/day). A second test trial was given after a single day ofextinction. This continued (test, extinction, and test) untilVNS-treated rats spent less than 20% of the test time freezing.

Repeated measures ANOVAs were used to compare extinction rate (percenttime freezing) across days and a Fisher's post-test were used toidentify effects across groups (VNS, sham, un-operated control). Allanimals showed some extinction to the conditioned stimuli, and theextinction was facilitated in VNS-treated rats compared to both controlgroups. Significant extinction was reached sooner in VNS-treated than incontrol rats.

In order to test the effect of VNS paired with extinction training on asecond measure of fear conditioning, an attempt to extinguishfear-potentiated startle was made. This task was used by Walker andcolleagues to demonstrate D-cycloserine enhancement of extinction inrats and led to the clinical trials of o-cycloserine as an adjuncttreatment with exposure therapy in humans suffering from PTSD andphobias. A total of 20 experimental, 20 sham, and 10 un-operated controlrats were included in this test of VNS effects on extinction offear-potentiated startle.

Rats were given about three consecutive days of about 10 min acclimationtrials in the experimental chamber. Stable baseline responses wereestablished about 24 hours (hrs) after the acclimation trials. Rats werepresented with thirty 95-decibel (dB) startle stimuli with an about 30 sinter-stimulus interval (lSI) for about two consecutive days. Thesebaseline startle stimuli reduced variability in startle responses duringtest trials.

About twenty-four hours after baseline was established, rats arepresented with 10 co-terminating (lSI 3, 4, or 5 min) light (3.7 s) andfoot-shock (0.4 mA, 0.5 s) pairings. About twenty-four hours later, ashort test was given to establish an initial percent fear-potentiatedstartle measure (light with startle−startle alone/startle alone×100).The startle response was measured by accelerometer activity transformedinto an analog electrical signal and transmitted to a programmable realtime processor to measure time over threshold (TOT). About twenty lightwith startle (3.7 s light, co-terminating 0.5 s startle stimuli) orstartle alone (0.5 s startle stimuli) probe trials were presented (30 slSI) in pseudo-random order.

No probe trial was repeated more than twice. Accelerometer wave data wasacquired from a real-time processor and stored for analysis by MATLAB(The Mathworks). About twenty-four hrs later, rats were presented with30 light (3.7 s) alone extinction exposure trials (lSI 30 s). Thisextinction trial was followed with vagus nerve stimulation (0.4 mA; 0.5ms biphasic pulses; 20 Hz, 30 s) delivered by a programmable RX7G-4stimulator base station and stimulator measuring time over threshold(TOT) and programmed in MATLAB (The Mathworks). About twenty-four hrsafter extinction training, rats were presented with 60 light-startle,startle-alone probe trials (lSI 30 s) in pseudo-random order. The effectof VNS on extinction was measured by an ANOVA comparing startle responseacross the three treatment groups, followed by a Fisher's post-test toidentify significant group effects.

A single day of extinction produces a minimal extinction against whichthe facilitation of treatment can be observed. Therefore, VNS-treatedrats were expected to demonstrate greater extinction than sham orun-operated controls. This enhanced extinction may be comparable withthe successful dose of o-cycloserine. Additional groups of 20experimental, 20 sham, and 10 un-operated control rats underwentauditory fear conditioning and extinction, however, the extinctiontrials were given about two weeks after initial training. VNSimplantations in rats remained viable for months. While about two weeksmay not seem like sufficient time to wait to begin therapy, it is asignificant amount of time relative to the lifespan of a rat (about 2-3years in the wild) and it is far longer than the more commonly useddelay of about 24 hrs. Percent of time spent freezing was quantified foreach rat and for each extinction trial.

Repeated measures ANOVAs were used to compare extinction rate (percenttime freezing) across days and a Fisher's post-test may be used toidentify effects of group (VNS, sham, un-operated control).

Of the two tasks, auditory fear conditioning was preferred because it isa simple task and can be used to address questions about the specificityof extinction to various cues. To determine the duration of theextinction effect, a single retention test was given about two weeksafter the last auditory fear conditioning extinction trial. Percent oftime spent freezing was quantified for each rat. Mean percent time spentfreezing was compared across groups of auditory fear-conditioned ratsusing an ANOVA with a Fisher's post test to identify significant groupeffects. Finally, conditioned fear was extinguished about two weeksafter rats were trained on auditory fear conditioning. The effect of VNSon extinction were measured by an ANOVA comparing freezing responseacross three treatment groups (VNS vs. sham controls), followed by aFisher's post-test.

Although the stimulation parameters proposed were optimized for memory,additional stimulation parameters were investigated, including changesin stimulation intensity (from about zero to about 0.8 mA), duration(about 100 ms to about 30 s) and frequency (about 10 to about 150 Hz)and bandwidth according to parameters optimized for cortical plasticity.Voltage controlled capacitive discharge was tested and was effective.Timing in relationship to the conditioning event and the use ofadditional and/or longer training times are also variables that may beoptimized.

The findings above indicate that exposure therapy can be enhanced byproviding an exposure therapy to a patient while simultaneouslystimulating the patient's vagus nerve. The nature of the exposuretherapy depends on the condition being treated. For example, forpost-traumatic stress disorder, the therapy event may be a sensoryrecreation of the traumatic event, presented in a controlledenvironment. The precise timing of the paired VNS pulse depends on thenature of the therapy event. The results indicate that the paired VNSpulse may be given during the therapy rather than before or after,although some overlap is not contraindicated. Where a trigger event canbe identified in the therapy event, such as a tone or flash, the pairingcan be derived from the trigger event. Exposure therapy of this kind canbe used to treat post-traumatic stress disorder, phobic disorders,obsessive-compulsive disorder, addiction disorders including addictionrelapse, and other memory extinction disorders. VNS can be pairedeffectively with any of these known therapies.

In an embodiment, a therapy method (for a patient having apost-traumatic stress disorder (PTSD)) includes: providing, to thepatient, an exposure event which is related to a traumatic event thatcontributed to the PTSD; and electrically stimulating the patient'svagus nerve during the exposure event. In an embodiment, said therapy isa memory extinction therapy. In an embodiment, said patient's vagusnerve is stimulated using a voltage controlled capacitive dischargestimulation pulse. In an embodiment, patient's vagus nerve is stimulatedelectrically with a stimulation intensity less than about 0.8 mA orabout 0.8 mA. In an embodiment, said therapy is an addiction therapy. Inan embodiment, said exposure event includes a trigger event thatindicates a paired vagal nerve stimulation. In an embodiment, saidexposure event contains sensory recreations of a traumatic event. In anembodiment, said patient's vagus nerve is invasively stimulatedelectrically. In an embodiment, the action of providing the exposure andthe action of stimulating the patient's vagus nerve during the exposureevent results in a reduction of the PTSD of the patient. In anembodiment, the patient is a patient where the PTSD took months todevelop following an initial exposure to a traumatic event that resultedin the PTSD. In an embodiment, the actions of providing exposure eventsand stimulating the patient's vagus nerve occur long after a traumaticevent that resulted in the PTSD. In an embodiment, the actions ofproviding exposure events and stimulating the patient's vagus nerve arepart of an extinction training regime, wherein the extinction trainingregime that is commenced two weeks after induction of an initial fearconditioning. In an embodiment, said patient's vagus nerve is stimulatedinvasively utilizing an electrical current from a device. In anembodiment, the actions of providing exposure events and stimulating thepatient's vagus nerve facilitate a natural extinction process of thepatient that protects most people from developing post-traumatic stressdisorder. In an embodiment, said therapy is a memory extinction therapy,the memory extinction therapy alleviating, at least in part, thepost-traumatic stress disorder.

In an embodiment, a phobia disorder therapy method includes: providing,to a patient, an extinction event which is related to something thatcontributed to the phobia; and electrically stimulating the patient'svagus nerve during the extinction event, thereby at least partiallyalleviating the phobia disorder. In an embodiment, the method furtherincludes: executing a retention test to determine a duration of anextinction of the phobia. In an embodiment, said patient's vagus nerveis invasively stimulated electrically. In an embodiment, said patient'svagus nerve is stimulated using a constant current stimulation pulse. Inan embodiment, said patient's vagus nerve is stimulated using a voltagecontrolled capacitive discharge stimulation pulse. In an embodiment, astimulation intensity is less than about 0.8 mA or about 0.8 mA. In anembodiment, a duration of the stimulation is about 100 ms to about 30 s.In an embodiment, a frequency of the stimulation is about 10 to about150 Hz. In an embodiment, the action of providing the extinction eventand the action of stimulating the patient's vagus nerve during theextinction event results in a reduction of the phobia disorder of thepatient.

In an embodiment, an obsessive-compulsive disorder (OCD) therapy methodincluding: providing, to a patient, a therapy event which is related tosomething that contributed to the OCD; and electrically stimulating thepatient's vagus nerve during the therapy event, wherein said patient'svagus nerve is stimulated electrically. In an embodiment, the action ofproviding the therapy event entails providing an exposure event to thepatient. In an embodiment, the action of providing the therapy event andthe action of stimulating the patient's vagus nerve during the exposureevent results in a reduction of obsessive-compulsive disorder. In anembodiment, said patient's vagus nerve is stimulated utilizing anelectrical current from a device.

In an embodiment, an addiction disorder therapy method includes:providing, to a patient, a therapy event which is related to somethingthat contributed to addiction-disorder; and electrically stimulating thepatient's vagus nerve during the therapy event. event; and wherein saidpatient's vagus nerve is stimulated electrically. In an embodiment, theaction of providing the therapy event entails providing an exposureevent to the patient. In an embodiment, the action of providing thetherapy event and the action of stimulating the patient's vagus nerveduring the exposure event results in a reduction of the addictiondisorder.

With reference to FIG. 4 , a neural stimulator system, in accordancewith an embodiment, is shown. A neural stimulator control 109 iscommunicably connected to a neurostimulator 128. Neurostimulator 128provides a stimulation pulse to a nerve 104 via a pair of electrodes 130a and 130 b. Electrodes 130 a and 130 b could be cuff electrodes,conductive plates or any other suitable neural stimulation electrode.The neurostimulator may be powered by a piezoelectric powering system aswell as near field inductive power transfer, far-field inductive powertransfer, battery, rechargeable battery or any other suitableneurostimulator power system. When neural stimulator control 109receives timing instructions from a timing control system (not shown),the neural stimulator control 109 initiates a stimulation pulse from theneurostimulator 128 via electrodes 130 a and 130 b.

With reference to FIG. 5 , a wireless neural stimulator system, inaccordance with an embodiment is shown. Neurostimulator 128 communicateswith the neural stimulation system 109 using an inductive transpondercoil 132. The neural stimulator system 109 includes an external coil134. Information may be communicated between the neural stimulatorsystem 109 and the neurostimulator 128. Power may be transferred to theneurostimulator 128 by the neural stimulator system.

With reference to FIG. 6 , a dual neurostimulator system, in accordancewith an embodiment, is shown. Two neurostimulator 128 may stimulateneural 104. The neurostimulators may be controlled to reinforce eachother, as redundancy, or to prevent efferent signals from projectingaway from the brain.

With reference to FIG. 7 , a multi-neurostimulator system. in accordancewith an embodiment, is shown. A plurality of neurostimulators 128 maystimulate nerve 104. The neurostimulators may be controlled to reinforceeach other, as redundancy, or to prevent efferent signals fromprojecting away from the brain.

None of the description in the present application should be read asimplying that any particular element, step, or function is an essentialelement that must be included in the claim scope: the scope of patentedsubject matter is defined only by the allowed claims. Moreover, none ofthese claims is intended to invoke paragraph six of 35 U.S.C. section112 unless the exact words “means for” are followed by a participle. Theclaims as filed are intended to be as comprehensive as possible, and nosubject matter is intentionally relinquished, dedicated, or abandoned.

At least one embodiment is disclosed and variations, combinations,and/or modifications of the embodiment(s) and/or features of theembodiment(s) made by a person having ordinary skill in the art arewithin the scope of the disclosure. Alternative embodiments that resultfrom combining, integrating, and/or omitting features of theembodiment(s) are also within the scope of the disclosure. Wherenumerical ranges or limitations are expressly stated, such expressranges or limitations should be understood to include iterative rangesor limitations of like magnitude falling within the expressly statedranges or limitations (e.g., from about 1 to about 10 includes, 2, 5, 4,etc.; greater than 0.10 includes 0.11, 0.12, 0.15, etc.). For example,whenever a numerical range with a lower limit, R₁, and an upper limit,R_(u), is disclosed, any number falling within the range is specificallydisclosed. In particular, the following numbers within the range arespecifically disclosed: R=R₁+k*(R_(u)−R₁) wherein k is a variableranging from 1 percent to 100 percent with a 1 percent increment, i.e.,k is 1 percent, 2 percent, 5 percent, 4 percent, 5 percent, . . . , 50percent, 51 percent, 52 percent, . . . , 75 percent, 76 percent, 77percent, 78 percent, 77 percent, or 100 percent. Moreover, any numericalrange defined by two R numbers as defined in the above is alsospecifically disclosed. Use of the term “optionally” with respect to anyelement of a claim means that the element is required, or alternatively,the element is not required, both alternatives being within the scope ofthe claim. Use of broader terms such as comprises, includes, and havingshould be understood to provide support for narrower terms such asconsisting of, consisting essentially of, and comprised substantiallyof. Accordingly, the scope of protection is not limited by thedescription set out above but is defined by the claims that follow, thatscope including all equivalents of the subject matter of the claims.Each and every claim is incorporated as further disclosure into thespecification and the claims are embodiment(s) of the presentdisclosure. The discussion of a reference in the disclosure is not anadmission that it is prior art, especially any reference that has apublication date after the priority date of this application. Thedisclosure of all patents, patent applications, and publications citedin the disclosure are hereby incorporated by reference, to the extentthat they provide exemplary, procedural, or other details supplementaryto the disclosure.

While several embodiments have been provided in the present disclosure,it should be understood that the disclosed systems and methods might beembodied in many other specific forms without departing from the spiritor scope of the present disclosure. The present examples are to beconsidered as illustrative and not restrictive, and the intention is notto be limited to the details given herein. For example, the variouselements or components may be combined or integrated in another systemor certain features may be omitted, or not implemented.

In addition, techniques, systems, subsystems, and methods described andillustrated in the various embodiments as discrete or separate may becombined or integrated with other systems, modules, techniques, ormethods without departing from the scope of the present disclosure.Other items shown or discussed as coupled or directly coupled orcommunicating with each other may be indirectly coupled or communicatingthrough some interface, device, or intermediate component whetherelectrically, mechanically, or otherwise. Other examples of changes,substitutions, and alterations are ascertainable by one skilled in theart and could be made without departing from the spirit and scopedisclosed herein.

The invention claimed is:
 1. A therapy method for a patient having apost-traumatic stress disorder (PTSD), the therapy method comprising:providing, to the patient, an exposure event which is related to atraumatic event that contributed to the PTSD; and during a therapysession which includes the exposure event, electrically stimulating thepatient's vagus nerve using a neurostimulator.
 2. The method of claim 1,wherein said therapy method is a memory extinction therapy method. 3.The method of claim 1, wherein said patient's vagus nerve is stimulatedusing a voltage controlled capacitive discharge stimulation pulse. 4.The method of claim 1, wherein said patient's vagus nerve is stimulatedelectrically with a stimulation intensity less than about 0.8 mA orabout 0.8 mA.
 5. The method of claim 1, wherein said therapy method isan addiction therapy method.
 6. The method of claim 1, wherein saidexposure event includes a trigger event that indicates a paired vagalnerve stimulation.
 7. The method of claim 1, wherein said exposure eventcontains sensory recreations of a traumatic event.
 8. The method ofclaim 1, wherein said patient's vagus nerve is invasively stimulatedelectrically.
 9. The method of claim 8, wherein the providing, to thepatient, an exposure event and the electrically stimulating thepatient's vagus nerve results in a reduction of the PTSD of the patient.10. The method of claim 1, wherein the patient is a patient where thePTSD took months to develop following an initial exposure to a traumaticevent that resulted in the PTSD.
 11. The method of claim 1, wherein theproviding, to the patient, an exposure event and the electricallystimulating the patient's vagus nerve occur long after a traumatic eventthat resulted in the PTSD.
 12. The method of claim 1, wherein: theproviding, to the patient, an exposure event and the electricallystimulating the patient's vagus nerve are part of an extinction trainingregime, and the extinction training regime is commenced two weeks afterinduction of an initial fear conditioning.
 13. The method of claim 12,wherein said patient's vagus nerve is stimulated invasively utilizing anelectrical current.
 14. The method of claim 1, wherein the providing, tothe patient, an exposure event and the electrically stimulating thepatient's vagus nerve facilitate a natural extinction process of thepatient that protects most people from developing post-traumatic stressdisorder.
 15. The method of claim 1, wherein said therapy method is amemory extinction therapy method, the memory extinction therapy methodalleviating, at least in part, the post-traumatic stress disorder.
 16. Atherapy method for a patient having a phobia disorder, therapy methodcomprising: providing, to the patient, an extinction event which isrelated to something that contributed to the phobia; and during atherapy session which includes the extinction event, electricallystimulating the patient's vagus nerve using a neurostimulator, therebyat least partially alleviating the phobia disorder.
 17. The method ofclaim 16, further comprising: executing a retention test to determine aduration of an extinction of the phobia.
 18. The method of claim 16,wherein said patient's vagus nerve is invasively stimulatedelectrically.
 19. The method of claim 18, wherein said patient's vagusnerve is stimulated using a constant current stimulation pulse.
 20. Themethod of claim 18, wherein said patient's vagus nerve is stimulatedusing a voltage controlled capacitive discharge stimulation pulse. 21.The method of claim 18 wherein a stimulation intensity is less thanabout 0.8 mA or about 0.8 mA.
 22. The method of claim 18, wherein aduration of the stimulation is about 100 ms to about 30 s.
 23. Themethod of claim 18, wherein a frequency of the stimulation is about 10to about 150 Hz.
 24. The method of claim 18, wherein the providing, tothe patient, an extinction event and the electrically stimulating thepatient's vagus nerve results in a reduction of the phobia disorder ofthe patient.
 25. A therapy method for a patient having anobsessive-compulsive disorder (OCD), the therapy method comprising:providing, to the patient, a therapy event which is related to somethingthat contributed to the OCD; and during a therapy session which includesthe therapy event, electrically stimulating the patient's vagus nerveusing a neurostimulator.
 26. The method of claim 25, wherein theproviding, to the patient, a therapy event entails providing an exposureevent to the patient.
 27. The method of claim 26, wherein the providing,to the patient, a therapy event and the electrically stimulating thepatient's vagus nerve results in a reduction of obsessive-compulsivedisorder.
 28. The method of claim 25, wherein said patient's vagus nerveis stimulated invasively utilizing an electrical current.
 29. A therapymethod for a patient having an addiction disorder, the therapy methodcomprising: providing, to a patient, a therapy event which is related tosomething's that contributed to addiction-disorder; and during a therapysession which includes the therapy event, electrically stimulating thepatient's vagus nerve using a neurostimulator.
 30. The method of claim29, wherein the providing, to a patient, a therapy event entailsproviding an exposure event to the patient.
 31. The method of claim 30,wherein the providing, to a patient, a therapy event and theelectrically stimulating the patient's vagus nerve results in areduction of the addiction disorder.